Aseptic cartridge and dispenser arrangement

ABSTRACT

A cartridge for use with a beneficial agent delivery device having a fillable reservoir. The cartridge includes a reconstitution, unit dose package having first and second compartments, and a fitment. The first compartment contains at least a first constintuent of the beneficial agent. The second compartment contains at least a second constituent of the beneficial agent. The fitment is disposed on the package for interfacing the package to the fillable reservoir.

TECHNICAL FIELD

The present disclosure preferably, but without limitation, generallypertains to disposable cartridges for use with drug delivery devices,and more specifically pertains to aseptic mixing cartridges for drugdelivery devices.

BACKGROUND

Medications, and in particular injectable medications, need to be storedsterile in aseptic commercial packages until the time of use. Somemedications are stored in prefilled single dose dispensing devices suchas prefilled syringes, for example the prefilled syringes from Vetter(Ravensburg, Germany). Yet most of injectable medication are stored inaseptic packages and are transferred to a dispensing device (i.e. drugdelivery device) shortly before use. The term dispensing device includewithout limitation hypodermic syringes, micro-needle syringes,micro-pumps, auto-injectors, jet injectors, topical dispensers,intradermal delivery devices, patch pumps, ear dispensers, oraldispensers, eye droppers, auto-injectors, infusers, or any other type ofdrug delivery device.

Several aseptic packages for storing injectable medications arecommercially available. Perhaps the most common aseptic package forinjectable products is glass vials. Some medications are stored inseparate components that are mixed just prior to use. Often this is doneto improve the medication's stability or to extend the medication'sshelf life. In one example the medication is a vaccine that is kept dryin one vial to extend the vaccine thermo stability; and a companion vialstores a dilutent that is dispensed to the vaccine vial via a syringeand needle prior to injection. In another example the medication is avaccine where one vial stored the formulated antigen and the second vialstores an adjuvant.

However, there are several drawbacks with this prior art: (a) thesepackages are many time costly and economically impractical to manyinjectable drugs such as vaccines; (b) where mixing of the medicationcomponents is required the process is complex and error prone; and (c)the transfer of the medication or its components from one container toanother or to the dispensing device is done in a non-sterile field andis prone to contamination risks.

U.S. Pat. No. 7,879,018 discloses one of several commercial and patentedkits for mixing an injectable dose. Here again the limitation of thedisclosure is the dependency on vials and the cost and complexitiesassociated with this type of glass primary containers.

Several commercial products and patents disclose a flexible package madefrom film or foils in which a product can be stored in an aseptic manneruntil the time of use. Some of these products and patents furtherdisclose a dispensing port communicating with the product in thedispensing package. In some cases a rupturable barrier is presentedbetween said port and the product to enhance the integrity of thepackage until the time of use. In some cases these flexible packagescomprise at least two product compartments that are mergeable prior touse to allow the substances from the different compartments to mix andform the dispensable product. These packages are sometimes referred toas pouches or sachet. One disadvantage of pouch packages is that it isrelatively challenging to efficiently express the entire content of thepackage. This is due to the dimensional ratio of these packages wherethe length and width are typically significantly larger than theperpendicular protrusion to their plane. This ratio is an inherentlimitation of the way pouch/sachet packages are formed. Pouches andsachets are formed from one or more flat film or foil (together “web”)that is sealed along its edges to form one or more receptacle. The pouchis filled during or post the receptacle formation and then sealed tokeep the product aseptically packaged.

When operated directly with the palm, one limitation of these relativelyshallow packages is that, when dispensing, the thumb of the operatorvery quickly bring two opposite walls of the package in contact at whichpoint the dispensing is halted. Sophisticated peristaltic action orfolding of the package would typically be necessary to expressadditional product from the package. In some arrangements, the flexiblepackage is depressed with a compression panel to cause the content toexpel. In these arrangements it is beneficial to operate the compressionpanel to depress a smaller contact surface of the product compartment,and hence allow developing more pressure. It is therefore advantageousto create a flexible dispensing package where the footprint of thecontent compartment is relatively small and the ratio between the sealedarea and the dimension of the package perpendicular to that surface issmaller.

In some applications, the deliverable medication requires a thorough mixof at least two substances prior to injection. In one example, a simplemethod is required to prepare a highly viscous water in oil (W/O) atpoint of use. At present, an emulsion is prepared by hand by mixingseparate oil and water components back and forth via three-way stopcockor a narrow tube connecting two syringes. The method is somewhat timeconsuming and often inconsistent. Connectors that have a porous membraneinside the syringes have been developed to provide more effectiveemulsion but at the expense of needing stronger pushing forceparticularly when pore diameter is decreased in order to shortenpreparation time. In addition the increased number of assembly anddismantle steps enhance the risks of operation errors and contaminationof the deliverable dose.

SUMMARY

At least some aspects of the present disclosure overcome thedisadvantages and limitations of the prior art by providing, forexample, a low cost, simple and easy to use cartridge. The cartridge, incertain configurations, allows for aseptic mixing and filling ofdispensers and in particular drug delivery injectors.

In some arrangement of the present disclosure, the package is made fromat least one web material wherein a first wall and a second wall of saidweb material are joined together along a boundary line of a compartment.In some arrangements the web material is pre-formed such that arelatively large volume of the compartment is achieved with a relativelysmaller sealing footprint. This pre-formed package may reduce theoverall dimensions of the package and improve storage and transportationefficiencies.

According to one arrangement of the present disclosure, a cartridgehaving a thin and flexible wall package comprises at least a firstconstituent compartment and a fitment for connecting the cartridge to afilling port of a dispenser. The fitment is attached to the package in afluid-tight fashion. The fitment may be attached to the filling port ofthe dispenser by one of the means, but is not limited to a Luerconnector, a Luer lock connector, a press-fit connector, a snap-onconnector, a snap, or a screw on cap.

In some arrangements, at least one cavity is pre-formed in at least oneof the web walls of the package, which provides a portion of at leastone product compartment of the package. This configuration allows asmaller ratio of the sealed area (footprint) of the compartment and thedimension of the compartment perpendicular to the sealed area (theswelling of the compartment), for storing the same volume of product.This configuration also permits a smaller footprint of the compartmentthan what would be required with a sachet/pouch package with a similarproduct volume. Forming of the web may be performed by one of the meansknown in the art, appropriate to the properties of the particular webmaterial including, for example, thermoforming, cold forming, formingwith preheat, plug-assist, pressure forming, vacuum forming, and acombination of the above.

In some arrangements, the package is constructed from a thin wall usingone of the forms known in the art including, for example, a blister, apouch, a sachet, a blow-molded container or an extruded container. Insome arrangements, the package may have more than one compartment forstoring a number of substances that need to be mixed prior to deliveryto a subject to form the dispensable product. The compartments may beseparated by a weak seal that can be broken by compressing at least oneof the compartments to exceed a threshold pressure of at least one ofthe substances that will cause the weak seal to separate (e.g., ruptureor peel) and allow the substances to mix. The package further comprisesan interface to the dispenser.

In some arrangements, the product is transferred from the cartridge tothe dispensing device. In some arrangements, the cartridge is replacedin the dispensing device. In some embodiments, the cartridge isconnected to the dispenser in an aseptic fashion at the manufacturingstage, thus no integration steps of the cartridge and dispenser arerequired by the user. This arrangement reduces the possibility for usererror or contamination of the device or the deliverable product as itavoids exposure to a non-sterile conditions prior or during thedispenser filling/loading process. In another arrangement, the cartridgeis stored separately from the dispensing device (i.e. syringe, injector,etc.) until the time of use. This arrangement may be advantageous wherethe drug needs to be stored and transported in a controlled environment,such as in controlled temperature refrigeration, and where packagingefficiency is important. This arrangement may also be advantageous toincrease logistic and user flexibility to select different sources andfashion of the delivery device.

In some arrangements, the dispensing device may be an injector. The terminjector may refer to various dispensing products includingmicro-infusion pumps or reservoirs such as, for example, pen injectors,reservoir assemblies, syringes, needle-free injectors, drug deliverydevices in general, patch devices, etc. More generally, the cartridge ofthe present disclosure is applicable for dispensing devices including,for example, ocular oral or ear droppers, spray or foam dispensers,topical applicators, and inhaler devices.

In another arrangement, a static mixer is disposed at the interfacebetween the cartridge device and the drug delivery device to enhance themixing and homogeneousness of the deliverable product. An example of astatic mixer is taught in U.S. Pat. No. 4,538,920, which is incorporatedherein in its entirety by this reference. In some arrangements thestatic mixer is constructed as a pattern of passageways formed betweenthe walls of the flexible walls by welding and performing a designatedareas of the walls. The static mixer may be merely a narrow nozzle, or aporous component accommodated in the flow passageway between thecartridge and the delivery device. In one arrangement, the static mixeris disposed in the cartridge port. In one arrangement, the cartridgecomprises more than one compartment holding different substances, whichare merged prior to transferring the content to the delivery device, andthe static mixer enhances the mixing of the substances as they aretransferred to the delivery device.

In some arrangements, the mixture may be transferred back and forthbetween the cartridge and delivery device to further mix the substances.In some arrangements, at least one substance is stored in the cartridgeand at least one substance is stored in the delivery device and thesubstances are transferred back and forth between the two to mix thesubstances. In one arrangement, the cartridge comprises at least a firstand a second compartment and at least one static mixer is disposedbetween the first compartment and the second compartment. Mixing may beenhanced by transferring the substances/mixture from one compartment tothe other compartment. At least one compression panel or an arrangementof compression panels may be operated with the cartridge to facilitatethe transfer of substances across the static mixer.

The present disclosure also relates to arrangements and methodsfacilitating efficient cartridge manufacturing and filling. In onearrangement, a compartment of the package is filled with fluid. Thecompartment is formed sealed leaving a designated passageway open thatleads to a port through which the fluid is introduced and the air isevacuated. Separate passageway for gas evacuation may be incorporated.The passageway may be constructed such that the fluid entering the portglides along the wall of the package, hence avoiding jetting, andminimizing foaming or air bubble formation, thus allowing increasedfilling rate.

In another arrangement, a liquid substance is frozen prior to fillingand is introduced into the package in a solid form. The temperaturearound the package and the heat transfer to the package during thefilling process is controlled such that the frozen liquid remainssubstantially solid until the compartment is sealed. The frozen liquidsubstance doze may be inspected in that form prior or during filling.This filling arrangement and method enhances the filling speed, and thesubstance inspection capability. In one arrangement, a dry powdersubstance has to be filled into the cartridge compartment. To facilitateproper filling of the powder, the powder is slightly compressed to forma loosely aggregated tablet and is filled in that form into thecompartment of the package. The tablet may be inspected prior or duringfilling to the cartridge. In one arrangement, after the tablet has beensealed in the compartment, the compartment is externally manipulated tode agglomerate the tablet thus improving the substance solubility at thetime of mixing with a dilutent. The external manipulation may be atleast one of, but not limited to, compression of the compartment,vibration including, for example, ultrasonic vibration, radio frequencyvibration, acoustic vibration, applying mechanical impact to thecompartment, and exposure to high or low temperatures.

The present disclosure further relates to arrangements that enhance thebarrier properties of the package by including a high barrier peelableopaque wall layer. The peelable high barrier layer may include analuminum laminate that provides the benefits of light blocking, andclose to absolute moisture and oxygen barrier. In order to have a visualinspection of the content of the cartridge prior to use, the highbarrier layer is peeled from at least a portion of the package, exposinga substantially see-through wall. In one arrangement the peelable layeris an integral layer of the web material from which the package is made.In another arrangement the peelable layer is applied to the see-throughwall during the cartridge manufacturing process. In one arrangement thepeelable layer is flat. In another arrangement the peelable layer ispre-formed to accommodate the form of the substance or compartment thatit is protecting. In one arrangement the peelable layer comprise aregistered adhesive coating selectively applied to the sealingcircumference of the peelable layer. In one arrangement the cartridge isin the fashion of a flexible clear-wall tube, and the peelable layer isarranged to wrap around the tube.

Another aspect of the present disclosure relates to a cartridge for usewith a beneficial agent delivery device having a fillable reservoir. Thecartridge includes a reconstitution, unit dose package having first andsecond compartments, and a fitment. The first compartment contains atleast a first constintuent of the beneficial agent. The secondcompartment contains at least a second constituent of the beneficialagent. The fitment is disposed on the package for interfacing thepackage to the fillable reservoir.

Another aspect of the present disclosure relates to an aseptic cartridgefor use with a beneficial agent delivery device having a fillablereservoir. The cartridge includes a package having at least a firstcompartment and a fitment. The first compartment contains at least oneconstituent of the beneficial agent, and the package is at leastpartially defined by a pre-formed flexible wall. The fitment is disposedon the package for interfacing the package in fluid communication withthe fillable reservoir.

A further aspect of the present disclosure relates to a cartridge foruse with a beneficial agent delivery device having a fillable reservoir.The cartridge includes a backing and a package assembly. The packageassembly includes at least a first compartment and a fitment. The firstcompartment contains at least one constituent of the beneficial agentand is at least partially defined by a flexible wall. The fitment isdisposed on said package for interfacing said package in fluidcommunication with the fillable reservoir.

Another aspect of the present disclosure relates to a cartridge for usewith a beneficial agent delivery device having a fillable reservoir. Thecartridge includes a package having at least a first compartment, afitment, and a coupler. The first compartment contains at least oneconstituent of the beneficial agent. The fitment is disposed on thepackage. The coupler is joined to the fitment for interfacing thepackage in fluid communication with the fillable reservoir.

A further aspect relates to a cartridge for use with a beneficial agentdelivery device having a fillable reservoir. The cartridge includes aunit dose package containing all of the beneficial agent or allconstituents thereof. The cartridge includes at least a firstcompartment containing all of said beneficial agent or at least oneconstituent thereof, wherein the first compartment is at least partiallydefined by a flexible wall. The cartridge also includes a fitmentdisposed on the package for interfacing the package in fluidcommunication with the fillable reservoir.

A further aspect relates to a pre-filled cap for enclosing anadministration portion of a unit dose beneficial agent delivery devicecomprising a unitary reservoir. The pre-filled cap includes at least afirst compartment containing at least one constituent of the beneficialagent, and a fluid passageway for communicating said first compartmentwith said administration portion.

A beneficial agent unit dose dispenser in accordance with the presentdisclosure includes a delivery device and a cartridge. The deliverydevice has a fillable, unit dose reservoir and at least one port incommunication with said fillable reservoir. The cartridge is asepticallyjoined to the delivery device and includes a unit dose package. The unitdose package includes at least a first compartment, a fitment, and anopenable seal. The first compartment contains at least one constituentof the beneficial agent, and the package is at least partially definedby a flexible wall. The fitment is joined with the unit dose package andinterfaces the unit dose package to the delivery device. The openableseal is disposed between the first compartment and the reservoir.

Another aspect of the present disclosure relates to a pre-filled syringefor dispensing a beneficial agent. The pre-filled syringe includes apiston assembly, a fillable barrel comprising an administration portion,and a pre-filled cartridge comprising at least a first compartmentcontaining at least a first constituent of the beneficial agent, and aflow passageway for communicating contents said first compartment tosaid barrel.

A further aspect of the present disclosure relates to a cap for anadministration portion of a delivery device. The cap comprises a fluidpassageway, a proximal end configured to communicate with saidadministration portion, and a distal end.

An example method in accordance with the present disclosure relates to amethod for forming a pre-filled package of a beneficial agent. Themethod includes providing a webbing having a first side and a secondside joined together to form a boundary of at least a first constituentcompartment therebetween, forming a frangible seal along at least aportion of said boundary, forming a permanent seal such that saidpermanent seal overlaps at least some of said frangible seal to createan overlapped portion having substantially the same sealing propertiesas said permanent seal, and filling the first constituent compartment.

Another example method in accordance with the present disclosure relatesto a method of forming a pre-filled package of a beneficial agent. Themethod includes forming a gas-filled compartment for the beneficialagent, forming a filling compartment having a filling port communicatingwith the gas-filled compartment via a first sealable channel, andforming an exhaust compartment having an exhaust port communicating withsaid gas-filled compartment via a second sealable channel. The methodalso includes coupling a source of at least a first constituent of thebeneficial agent with said filling port in a fluid tight fashion,filling said gas-filled compartment from said source via said fillingchannel while evacuating gas through said exhaust port, and sealing saidfirst sealable channel and said filling channel.

A further method incordance with the present disclosure relates to amethod of producing a unit-dose delivery device for a beneficial agentthat includes receiving an assembled delivery device, receiving apre-filled, aseptically sealed cartridge which has been prefilled withat least a first constitutent of the beneficial agent, and integratingsaid delivery device and said aseptically sealed cartridge.

Another example method relates to filling a package with a unit-dose ofbeneficial agent in a liquid state. The method includes freezing ametered unit-dose of said beneficial agent in a mold to create a frozendose, placing the frozen dose in a semi-finished compartment, andsealing said compartment.

Another example method relates to filling a package with a metered doseof at least a first constituent of a beneficial agent in a flowablesolid material form. The method includes metering a dose of the firstconstituent, compressing said metered dose enough to form a unitarybody, placing said unitary body in a semi-finished package, sealing thepackage, and directing energy at the unitary dose through a wall of thepackage to transform the unitary dose into a particulate.

The applications of the present invention are not limited to drugdelivery, which is provided herein by way of example. The teachingsdescribed herein can be applied to dispensing devices in other areassuch as, for example, glue dispensing, chemicals dispensing, etc. Thepresent disclosure provides various configurations for accomplishingthis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1a to 1f illustrate an injector cartridge assembly with a blisterpackage associated with its cap, which can be employed to variousconfigurations;

FIGS. 2a and 2b illustrate a syringe assembly with a blister packageassociated with its cap, which can be employed to variousconfigurations;

FIGS. 3a and 3b illustrate a prefilled syringe assembly with a packageassociated with its piston's stem, and extending axially from it, whichcan be employed to various configurations;

FIG. 4 illustrates a syringe assembly with a blister package associatedwith its stem, and extending laterally from it, which can be employed tovarious configurations;

FIGS. 5a and 5b illustrate a prefilled cartridge in a spring poweredneedle-free auto injector;

FIG. 6 illustrates a prefilled cartridge in a pyrotechnically poweredneedle-free auto injector

FIG. 7 illustrates a cartridge made from an extruded tube;

FIG. 8 illustrates a cartridge made from extruded tube, loaded in aneedle-free auto-injector;

FIG. 9a illustrates a cartridge made from extruded tube, mounted onto asyringe;

FIG. 9b illustrates a cartridge made from extruded tube comprising apeelable protective foil, mounted on a syringe

FIGS. 10a to 10e illustrate a cartridge with a peelable portion of theformed-wall and a an extended walls portion forming an asepticcompartment around the dispensing port, and a number of operation steps;

FIG. 11 illustrates a cartridge with a peelable portion of the flatwall;

FIG. 12 illustrates a cartridge with a flanged dispensing port attachedto the external side of the wall of the cartridge;

FIG. 13 illustrates a cartridge associated with a valved-couplercommunicating to a syringe and a needle;

FIG. 14 illustrates a cartridge associated with the distal end of asyringe barrel;

FIG. 15 illustrates a semi-finished cartridge ready for lyophilizationof a beneficial agent;

FIG. 16 illustrates a cartridge comprising a static mixer at itsdispensing port facilitating the mixture of two constituents stored inthe cartridge;

FIG. 17 illustrates a system for mixing a first constituent contained ina cartridge and a second constituent contained in a syringe;

FIG. 18 illustrates a system for mixing a first constituent and a secondconstituent contained in a cartridge;

FIG. 19 illustrates a static mixer integrally formed in a blister typecartridge;

FIGS. 20a to 20e illustrate a method for fabrication the cartridge;

FIGS. 21a to 21e illustrate a syringe comprising a static mixing formixing a substance contained in a syringe with a substance contained ina cartridge.

FIGS. 22a and 22b illustrate a cartridge communicating with a stakedneedle syringe via a fitment;

FIGS. 23a to 23f illustrate a cartridge and a staked needle syringeattachable via a coupler; and

FIG. 24 illustrates another arrangement of a staked needle coupler;

FIGS. 25a to 25c illustrate a cartridge comprising a coupler containingan injection needle

FIG. 26 illustrates the cartridge adopted for a syringe with anintradermal (ID) injection adapter

FIGS. 27a and 27b illustrate a cartridge associated with an ID syringe

FIG. 28 illustrates another arrangement of a cartridge associated withan ID syringe

FIGS. 29a and 29b illustrate another arrangement of a cartridgecomprising an ID needle arrangement

FIG. 30 illustrates another arrangement of a cartridge comprising an IDneedle arrangement

FIGS. 31a and 31b illustrate a cartridge comprising a needle safety anddisabling features.

FIG. 32 illustrates a cartridge with a movable needle

FIGS. 33a to 33e illustrate a prefilled syringe arrangement

FIG. 34 illustrates a cartridge with a backing and walls protecting theprefilled package of the cartridge.

FIG. 25d is showing the two sub assemblies of the prefilled cap

FIG. 25e is showing an exploded view of the cap portion of a cartridge

FIGS. 3a and 3b number 39 is showing a fitment

FIG. 4 number 49 is showing a fitment

FIG. 15 the second compartment is hermetically scaled empty and can befilled via filling arrangement 152 as will be described in Figure

FIG. 20f is showing the frangible seal pattern 401

FIG. 20g is showing the permanent seal pattern 402 partly overlappingthe frangible seal

DETAILED DESCRIPTION

FIG. 1a shows an arrangement of an injector 11 and a cartridge 10. Thefigure provides the section line for the section view of FIG. 1b . FIG.1b illustrates a section view of an injector assembly 11 and a cartridge10. The injector 11 comprises a body 13 in a form of a barrel and apiston 14 disposed in said body and is moveable along the axis of thebody between a forward, empty state, and a retracted, filled states. Thepiston 14 further comprises an O-ring seal 14′, providing a fluid tightseal between the body and the piston, and defining a compartment infront of said piston for receiving a fluid dose. The compartment isshown at the emptied state, where the piston is advanced to the forwardmost position in the body 13. A jet nozzle 17, at the front of the bodyprovides a port for filling a fluid dose to the injector 11, and forhypodermically delivering said dose to a subject in a needle-free jetinjection fashion.

The cartridge 10 comprises a first thin wall 18′, formed to provide twocavities; and a second thin wall 18″ which seals against the first thinwall 18′ to define a first sealed compartment 15 and a second sealedcompartment 16. A fitment 12 is attached to the package between thefirst wall 18′ and the second wall 18″. The fitment 12 is structured toengage with the front of the injector body 13. A first frangible sealsection 19′, separates between the first compartment 15 and the secondcompartment 16, and is peelable by a defined threshold force. A secondfrangible seal 19″ separates between the second compartment 16 and thefitment 12, and is peelable at a defined threshold peeling force. Thethin walls 18′ and 18″ may be made from a type of film or foil (togetherreferred to as “web” or “web material”) including extruded web, blownweb, cast web, multilayer web, laminated web, coated web, webs includingmetalized layers such as aluminum layer, webs including metal oxidelayers such as alumina or silica, webs including high barrier layerincluding Cyclic Olefin Polymer (COP), Cyclic Olefin Copolymer (COC),polychlorotrifluorocthylenc (PCTFE), Ethylene Vinyl Alcohol (EVOH). Theinner adhesive layer of the web material may be made from Olefinionomers, Ethylene-vinyl acetate (EVA) or other materials.

It may be advantageous to incorporate an adhesive layer to the web thathave a controlled peeling force such that designated areas of thecircumferential seal around the compartment would have lower peelingforce than others, thus limiting the areas that will be ruptured when athreshold peeling force is applied to the seal area between the firstwall 18′ and the second wall 18″. One such adhesive layer is the ionomerbland brand EZ Peel® (Bemis, Neenah, Wis.) which produces a peelableseal at sealing temperature of 130° C., and a permanent non-peelableseal at sealing temperature of 170° C., thus allowing a good control ofthe sealing properties by performing a two stage welding process atdifferent temperatures.

Another approach to accomplishing a desired sealing force patternbetween the first wall 18′ and the second wall 18″ is to have the innerlayer of the web made with a selective adhesive pattern of at least twoadhesive types with different peeling strength. The fitment 12 may bemade from an olefin polymer that will have good adhesion to the innerlayer of the web. In some arrangements the fitment is attached to theouter side of one of the first wall 18′ or the second wall 18″, and athrough hole in the web communicates the content of the cartridge 10 andthe fitment 12. In this arrangement the fitment material should becompatible for attachment to the web's outer layer material. Thecartridge compartments 15, 16 may contain various substances. In oneembodiment, the first compartment 15 contains a dilutent and the secondcompartment 16 contains a beneficial agent in dry format, and thecontent of the two compartments needs to be mixed to form a dispensableproduct dose. In one embodiment, the first compartment 15 contains adilutent such as saline or water for injection, and the secondcompartment contains a vaccine in dry powder format.

The content of the first compartment 15 and the second compartment 16may be in various forms including liquid, gel, paste, slurry, solid,granules, pellets, flowable powder, compressed powder, a cake, alyophilized cake, or other forms known in the art. When the firstcompartment contains a fluidic material, the first frangible seal 19′may be separated by depressing the first compartment 15 and pressurizingsaid content, thereby applying force to the first frangible seal 19′ andpeeling apart the seal, creating a joined compartment betweencompartment 15 and compartment 16, and allowing the content of the twocompartments to mix. The second frangible seal 19″ may be ruptured bydepressing the joined compartment and pressurizing its content there bycausing a peeling force to the second frangible seal 19″.

FIG. 1c shows the cartridge 10 mounted on to the injector 11. Thefitment 12 is engaged with the front end of injector body 13, preferablycreating an aseptic zone within the fitment area. A passageway offitment 12 and the injector nozzle 17 are in fluid communication. Forparenteral hypodermic drug delivery applications, all the areas of thedevice that come in contact with the deliverable substances and theareas that will come in contact with the body of the subject need to bemaintained sterile until the time of use. In the arrangement of FIG. 1c, the aseptic engagement of the injector 11 and the cartridge 10maintains the sterility to that area. The sterility of the inner side ofthe barrel 13 may be maintained through a second seal at the back end ofthe body 13, a local overwrap of portions of the back of the body 13 andthe piston 14, or a sterile overwrap to the entire device. Similarsolutions will apply to the arrangement of FIG. 1b with the additionthat aseptic covers would be needed for the front area of the injectorbody 13 and the fitment 12.

The sterility of the fitment 12 may be achieved with a lead or a capprotecting the port area. A foil lead may be heat-sealed to thecircumference of the vertical walls around the port. In one embodiment,the cartridge 10 is stored in a sterile overwrap. In some embodiments,wherein at least one of the substances is in dry format it may beadvantageous to include a drying agent such as a desiccant capsule,pellets, or gel in the sterile overwrap, to avoid moisture frommigrating to the dry compartment across the web 18, 18′ wall. In oneembodiment, the drying substance may be integrated in the web (thisarrangement is sometime referred to as scavenger film). Packaging thecartridge separate from the injector will improve thecontrolled-conditions storage and transportation of the drug product.The sterility of the front end of the body 13 in the arrangement of FIG.1b can be achieved in various ways including a tight cap, a thermallysealed foil around the nozzle 17 area, and by packaging the entireinjector in a sterile overwrap. The arrangement of FIG. 1c may thereforebe advantageous to reduce the measures that need to be taken to maintainsterility of the product.

Referring now to FIG. 1d , the arrangement of FIG. 1c is shown after thefrangible seals (19′ and 19″ in FIG. 1c ) have been ruptured, and ajoined compartment 16′ is formed in fluid communication with thepassageway of fitment 12.

FIG. 1e shows the arrangement of the previous FIG. 1d , when the pistonis retracted from the body 12, causing the fluid from the joinedcompartment 16′ to flow into the injector 11.

FIG. 1f shows the arrangement of the previous FIG. 1e where the piston14 is in a fully retracted state. The joined compartment 16′ is fullydepleted, and its content is fully transferred to the injector 12. Thecartridge 11 is removed and the injector 12 is now loaded with thedeliverable product dose and is ready to use. Where the arrangement ispre-sterilized, the front portion of the injector was maintained sterileuntil this point where the fitment 12 is removed. This arrangement maybe advantageous compared to commercially available arrangements whereinthe injector's application surface is exposed to non-sterile field evenbefore the injector filling step, increasing contamination risk to thesubject.

The present arrangement is showing an aseptic filling arrangement of ajet injector cartridge. In further arrangements of the presentdisclosure, a similar arrangement is provided to fill other cartridges,dispensers, or drug delivery devices known in the art including, forexample, intramuscular, subcutaneous, or intradermal injectors, andtheir cartridges, topical applicators and their cartridges andreservoirs, infusion pumps, micro-infusion pumps, infusers,micro-infusers, patch delivery devices, and their cartridges andreservoirs, infusion containers including infusion bags and infusionbottles, oral, ocular, or ear dispensers and their cartridges andreservoirs, glue dispensers, and other dispensers, delivery device andapplicators for various form of use and purpose.

FIG. 2 illustrates an arrangement of a prefilled mixing cartridge 10 anda regular syringe 20. The figure provides a section line of the sectionview of FIG. 2b . Referring to FIG. 2b , the cartridge 10 comprise afitment terminating with a Luer Lock female connector, coupled with aLuer Lock male connector of the syringe 20, and forming a fluid tightconnection between the cartridge 10 and the syringe 20. The fluid may betransferred from the cartridge 10 to the syringe 20 in the same fashionas with the injector of FIG. 1. The Syringe tip will remain in anaseptic environment until the time of use where the cartridge 10 will beremoved. This arrangement may be advantageous compared to commercialproducts where the syringe tip or the tip of a needle are exposed to nonsterile field prior to the filling step, which increases the risk ofcontamination to the subject. In one arrangement, the cartridge ismaintained separate from the syringe until the time of use, when theyare integrated through the Luer coupling. To maintain the sterility ofthe syringe 20 and the cartridge 10, similar arrangements and measuresmay be taken as described above for the arrangement of FIG. 1 b.

Referring to FIG. 3, another arrangement is provided wherein thecartridge is associated with the back end of the piston 31. The piston31 comprises a fluid passage 32 along its axis, communicating thecartridge port 9 and the syringe body. At the front end of the piston 31a plunger 34 is arranged such that when the piston 31 is retracted, thefriction of the plunger 34 with the barrel 33, cause the plunger 34 toslightly displace away from the piston 31, thereby open a fluid path 35(see arrow) allowing the content of the cartridge to transfer into thebarrel 33. A cap 37 maintains an aseptic space around the syringe'sdispensing tip 36. FIG. 3b illustrates the arrangement of FIG. 3a afterthe piston 31 has been retracted to the fully retracted position and isbeing advanced. The cartridge 10 is completely depleted of its content.The plunger 34 is replaced at the closer position to the piston 31 headthereby sealing the passageway 32, such that the content of the barrel33 can only advance to the syringe port 36 when the piston 31 isadvanced.

Unlike commercial syringes where the dispensing tip or a needleassociated with it, are exposed to non sterile field prior to thefilling process, in the current configuration the cap is removed fromtip 36 just prior to use, and only after the filling process. Thecartridge may be coupled with the syringe by various means known in theart including, for example, Luer connector, barb connector, press fitconnector, a septum arrangement, a coupling tube, or adhered to eachother. In one arrangement, the cartridge is disposed inside a hollowspace in the piston.

Referring now to FIG. 4, an arrangement is illustrated where thecartridge 10 is connected to the back end of the piston 43, andextending in a lateral direction from piston 43. A valve 44 is disposedat the back end of the fluid passageway 42 allowing fluid to transferfrom the cartridge 10 to the barrel 40, but prevents fluid from flowingin the opposite direction, thus causing the entire dose to flow only tothe dispensing tip 45 when the piston is advanced. In one arrangementthe piston 44 also allows air into the flow passageway 42 after thecartridge 10 is emptied thus advancing the fluid from the passageway tothe barrel. In one embodiment, a dedicated aseptic compartment allowsair of water into the fluid passageway 42 after the beneficial agent thecartridge is emptied from the beneficial agent, to wash the passagewayfrom the residual beneficial agent. In one arrangement said water or aircompartment is part of the cartridge 10 assembly.

FIG. 5a illustrates a jet injector comprising a cartridge 10 disposed ina pressure chamber 51 in the injector body 52. The cartridge 10comprises a needle-free jet nozzle 17 associated with the front end ofthe injector body. A piston 53 is disposed in the body 52 and isdetained in its peruse position by detaining mechanism (not shown), andis biased forward to deplete the volume of the pressure chamber 51. Inone arrangement, the cartridge 10 comprise more than one compartmentprior to use, and those are manually mixed by removing the cartridge 10and following a similar procedure as described in FIG. 1; then replacingthe cartridge 10 in the body 52.

FIG. 5b shows the injector 50 after the piston 53 has been released fromthe detent mechanism and has been forced forward by spring 54 andpressurized the pressure chamber 51, thereby causing the cartridge wallsto collapse and express the content of the cartridge 10 through nozzle17. The nozzle 17 may be protected by an aseptic cap or adhered foiluntil the time of use.

FIG. 6 shows a similar arrangement to that of FIG. 5 with the exceptionthat the piston is biased forward by pressurized gas, generated by apyrotechnic module 61 when the last is activated by manual switch 62.

FIG. 7 shows a cartridge 70 made from a tube section 71 that is pinchedand heat sealed 72 across the tube section 71 in a number of locations72 along the tube section 71 to form at least one compartment comprisinga beneficial agent. In one configuration of the cartridge 70 the sealsat the pinching locations 72 are frangible seals made such that theywill peel apart under the presence of threshold pressure or force. Thetube section 71 may be made by extrusion, injection molding, blowmolding or other manufacturing methods known in the art. In onearrangement, the tube section 71 comprises a number of layers where theinner layer is a heat sealing material and at least a second layerprovides improved barrier properties to reduce transfer of certaingasses or moisture across the tube wall. In one arrangement, the tube isco-extruded. In one arrangement, at least one first layer of the tubewall is made from a rolled sheet of plastic, metal, or metal oxide, andat least one second layer is extruded over said rolled first layer.

FIG. 8 shows a needle free jet injector arrangement similar to thearrangement presented in FIG. 5, with the exception that the cartridge80 is made from a tube section, to which a jet nozzle 17 is attached toits front end.

FIG. 9a shows a syringe and cartridge assembly similar to thearrangement presented in FIG. 3, with the exception that the cartridge90 is made from a tube section 90 in pinched and sealed across in twopoints 99′ and 99′″ to form a compartment. Seal 99′ is a frangible sealthat would rupture when the cartridge is compressed and the content ispressurized, to allow fluid communication between the syringe and thecartridge to which a female Luer Lock connector 92 is attached at itsend. The tube section in some arrangements the cartridge 90 may bemaintained separate from the syringe until the time of use. Sterility ofthe product and the device may be accomplished in similar fashion andmeasures as described in FIGS. 1 to 3 above. The tube wall mayincorporate a single layer or multi layers and may incorporate a highbarrier PCTFE layer, an aluminum layer, a COC layer, and a peelableadhesive layer

FIG. 9b shows a further arrangement where of a cartridge made from tubewhere a first seal 99′ and a second seal 99″ define a first compartment95, and the second seal 99″, holding a first substance, and a third seal99′″ define a second compartment 94 holding a second substance. Thesecond seal 99″ is rupturable upon pressurizing either or both of thefirst compartment 95 and the second compartment 94; to allow the firstsubstance and the second substance to merge. The first seal isrupturable to establish fluid communication between the cartridge and asyringe 97. The cartridge further comprises peelable barrier shells 96′and 96″ sealed to each other and across the first and second pinchedseal sections 99′ and 99″; enhancing the barrier between the cartridgesurrounding and the first compartment 95. This arrangement may beparticularly advantageous where the barrier properties of the tube 93are insufficient to protect the first compartment 95 from moisture,oxygen or light transmission.

The tube material may preferably be transparent to allow visualinspection of the contents, which generally compromise some of thebarrier properties. The peelable shells may include a high barrieraluminum layer that prevent visual inspection of the cartridge contents,and hence the need to peel the shells for inspection. A first tab 98′and a second tab 98″ are provided as extensions to the first and secondpeelable shells 96′ and 96″, respectively, to facilitate the peeling ofthe shells with the fingers. The peelable shells may be pre-formed toaccommodate the shape of the first compartment 95. At least one of thepeelable shells 96′ and 96″ may be extended to form a barrier shell tothe second compartment 94. At least one of the peelable shells may beextended to provide a printable, or otherwise markable, surface,including graphics, text, barcode or other optical machine-readablerepresentation of data, which shows data about the content of thecartridge, operation instructions, warnings, etc. The peelable shellsmay be made from a single or multi-layer film or foil (together “web”)and may include a pressure sensitive adhesive, electrostatic adhesive ortemperature sensitive adhesive to form the peelable seal.

FIG. 10a shows another preferred arrangement 100 in which the secondcompartment 16 comprises a peelable layer 105. For various applicationsit is desired to have at least a portion of the package made from aclear material, for instance, in application where it is desired tovisually (or by optical instrumentation) inspect the content of one ormore compartments, or the merged compartment after combining the contentof two or more compartments. However typically clear materials havehigher moisture vapor transmission rate (MVTR) than foils, which areopaque, providing lower barrier between the compartment(s) and thesurrounding of the package. Some products are extremely sensitive tomoisture such as dried vaccine with which potency may be compromisedwith relative humidity levels higher than 2% or 3%. Yet visualinspection of the vaccine powder is important prior to use to ensurethat the product has not been tampered; and after mixing, to inspectcomplete dissolution of the vaccine powder with the dilutent.

In one arrangement of this disclosure the cartridge is stored in adesiccant containing overwrap, keeping dry environment around thecartridge. In one arrangement, the overwrap material is of the typeknown in the industry as “scavenger film” in which a desiccant substanceis embedded in the composition of the web material. In FIG. 10a thepowder compartment of the package 100 comprises a peelable high-barrierformed layer 104, which is opaque, or has limited optical transparency.In some arrangements, the peelable layer may provide a barrier fromlight. High barrier clear materials are typically more costly than lowbarrier clear materials. In some arrangements, the localized, peelablelayer 104 is made from high barrier clear material such as a filmcontaining an Aclar (Honeywell), while the larger, formed-wall of thepackage 18′ is made from a low barrier material to reduce manufacturingcosts. The peelable layer 104 may provide other desired properties thatthe formed-wall 18′ lacks. The peelable layer 104 may be part of thecomposition of the raw material that the formed-wall 18′ is made of. Thepeelable layer 104 may be made from a separate web of the first wall18′, and in one manufacturing arrangement, the two webs are formedtogether. In some arrangements, where the wall 108′ is a thermoformablefilm, and the peelable layer 104 is a cold-formed foil, the formingprocess may involve a step combining cold forming and thermoforming.

In some arrangements, the cavity 105 in the peelable layer 104 is formedseparate from the formed-wall 18′ and is subsequently attached to thepackage in a sealed fashion. Attaching the peelable layer 104 to thepackage may be achieved by one of the means known in the art includingan adhesive, a glue, pressure sensitive adhesive, heat stake welding,ultrasonic welding, etc. In one arrangement, the peelable layer 104 issealed to the first wall 18′ via a die-cut adhesive sheet. The die-cutadhesive may be adhered to the first wall 18′, and at a subsequent stagethe peelable layer 104 is attached to it. Alternatively, the die-cutadhesive may be adhered to the peelable layer 104, and at a subsequentstage the first wall 18′ is placed attached to it. The peelable layer104 may comprise an aluminum lamination or aluminum coating.

The arrangement 100 further comprises a dispensing port compartment 103maintaining the dispensing port in an aseptic enclosure until the timeof use. The dispensing port compartment 103 is formed in an extension101 of the web materials of the package 100. A tear-off notch 102provides for an easy removal of extended portion 101 exposing thedispensing port. FIG. 10b shows the arrangement 100 after the peelablelayer 104 has been removed, allowing for visual inspection of thecontent of the second compartment through the clear wall 18′. Inaddition, extension 101 has been removed, exposing a dispensing port 12in the form of a female Luer Lock connector. In some procedures it willbe desired to merge compartments 15 and 16 prior to removing extension101 to minimize the exposure of the dispensing port and reduce the riskof contamination. The second wall 18″ of the package 100 is preferablymade from high barrier material such as a laminated aluminum foil, SiOxlaminate, AlOx laminate or other materials known in the art.

In some arrangements the second compartment 16 is depressed to rupturethe first barrier 19′ between the first compartment 15 and the secondcompartment 16, to cause the two compartments to merge; and to rupturethe second barrier 19″ between the second compartment 16 (or the mergedcompartment (15+16). The pre-formed structure of the second compartment16 allows controlling the rupture of each of barriers 19′ and 19″ at adesired sequence and timing. The deep form of compartment 16 providesthat when the compartment 16 is depressed at its distal end 106, thestrain in this area 106 of the first wall 18′, and the seal of the firstwall 18′ and the second wall 18″ proximal to this area 106 is relaxed;while the proximal area 109 of the first wall 18′ opposite to thedepression zone 106, and the seal between the first wall 18′ and thesecond wall 18″ proximal to that proximal area 109 is strained;resulting in rupture of the first barrier 19′, while the second barrier19″ remains intact.

At a subsequent step, the merged compartment (not shown) is pressed atits proximal area to excess the strain on second frangible seal 19″causing it to rupture and establish fluid communication between themerged compartment and the dispensing port. In addition to, or as analternative to the aseptic dispensing port compartment 103, the port maybe aseptically sealed with a plug (such as a male Luer Lock cap), awelded foil portion, a stopper (such as a rubber stopper, or by anyother means known in the art. The second frangible seal may be avoidedif other sealing features are aseptically protecting the content andpreventing it from spilling.

FIG. 10c to FIG. 10e show one way of operating the cartridge 100 toachieve a controlled and sequenced rupture of the frangible seals 19′and 19″ by direct operation of the thumb of the operator. The cartridge100 is resting in the palm of the operator on the index finger and themiddle finger. In FIG. 10c the second compartment 16 is depressed bythumb on its distal portion 106. As a result the wall 18′ at theproximal area 107 of the first compartment 16 is strained exertingpeeling force to the first frangible section 19′. At the same time thedepression of the thumb on the distal area 106 of the second compartment16 prevent strains from that area of the first wall 18′, thus thepeeling force on the second frangible section 19″ is eliminated orminimized. As a consequence, shown in FIG. 10d , the first compartmentand the second compartment become merged compartment 16′ while thesecond frangible seal 19″ remains intact, allowing the substances of thetwo compartment to mix prior to communicating the dispensable productwith the dispensing port. The configuration of FIG. 10d allows puttingthe cartridge aside, for example in order to let the substances to mixproperly, without exposing to contamination risks, as the dispensingport is still sealed in the dispensing port compartment 104, and themerged compartment 16′ is still not in communication with the dispensingport.

In FIG. 10e the dispensing port compartment has been tore off and theport 12 is engaged with a syringe 108. The merged compartment 16′ isdepressed with the thumb at its proximal end 107 causing the wall at thedistal end 106 of the merged compartment to strain and exert peelingforce on the second frangible seal 19″, causing it to rupture andestablish fluid communication between the syringe 108 and the mergedcompartment 16′ via the dispensing port 12. In other arrangements, thedepression of the compartments is done by a compressing object such as aflat panel or a roller. This disclosure advantageously teaches a drugcartridge for filling an injector where the fluid communication betweenthe cartridge and the injector is established only after the injectorand the cartridge have been secured in a sealed tight fashion, limitingthe exposure of the injectable product to non-sterile field, andreducing the risk of the product spillage. Typically with vials andampoules the fluid communication is established during the integrationof the injector and the cartridge, typically by a spike penetrating aseptum seal.

FIG. 11 shows an arrangement where the second wall 18″ of the packagecomprises a peelable layer 111, providing enhanced moisture barrier tothe substances in the compartments. The formed-wall 18′ is preferablymade from a cold formed aluminum laminate providing a high barrier tomoisture and gasses. A tab 112 provides an easier peel of the secondwall 18″. In some arrangements, the peelable layer 111 is attached tothe second wall 18″ by one of the means known in the art such as weldingor adhesion. In one arrangement, the peelable layer 111 is a label witha pressure sensitive adhesive. In some arrangements, the pressuresensitive adhesive is selectively disposed on the label such thatcertain areas of the label are free from the pressure sensitiveadhesive.

The peelable layer preferably comprises an aluminum layer providing ahigh barrier to moisture and gasses until it is being peeled off. Insome arrangements, the peelable layer is part of the multi-layermaterial composition of the web that makes the second wall 18″. In somearrangements, the peelable layer is removed from the entire second wall18″. In some arrangements, a scored or die-cut pattern defines the areaof the peelable layer 111 that will be removed. In some arrangements, ascored section of the first wall 18′ and the second wall 18″ is scoredor die-cut, providing a tab, or a break-off tab that facilitates theremoval of the peelable layer 111. The cartridge 110 may be readilyattached to an injector, a drug delivery device, a reservoir of these orother systems, or it may comprise a closure that is removed prior touse. The peelable layer 11 may include printed (or otherwise marked)information and may be attached to a person, a device, the drug deliverydevice receiving the content of the cartridge 110 (such as a syringe),or a document after it has been peeled off from the cartridge 110, as alabel presenting that information.

It is understood that other labels may be attached to the cartridgearrangements according to this disclosure, said labels may includeprinted or otherwise marked information; and may be non-peelable orpeelable and further attached to other objects such as a person, adevice, or a document. In some arrangements, an information containingportion of the cartridge may be tearable or otherwise detachable fromthe rest of the cartridge in order to include or present thisinformation else where such as on a document, attached to a patient, orto a device.

FIG. 12 shows an arrangement where the dispensing port is attached tothe external side of the second wall 18″ via a flange 121. The flangecomprises a conduit (not shown) aligned with an opening in the wall 18″(not shown) which communicates the content of the package with thedispensing port. The port 12 is attached to the wall 18″ by one of themeans known in the art including heat welding or adhesion. The cartridge120 may be readily attached to an injector, a drug delivery device, areservoir of these or other systems; or it may comprise a closure thatis removed prior to use.

FIG. 13 shows an arrangement where the cartridge 133 is associated witha manifold 134 disposed between a syringe 131 and a needle (shown herecovered by a needle shield 132). The manifold comprises a valvearrangement which, after the cartridge 133 has been activated, draws thecontent of the cartridge 133 into the syringe 131 when the syringe'spiston is retracted; and delivers the content of the syringe 131 to theneedle when the piston is forwarded. In some arrangement a manipulationof the manifold will cause disengagement of the cartridge from themanifold 134 when shifting from a dose drawing configuration to a doseinjection configuration. U.S. Pat. No. 7,879,018 teaches a number ofmanifold arrangements for accomplishing the same and is incorporatedherein in its entirety by this reference.

The arrangement of this FIG. 13 discloses a unique arrangement of aprefilled syringe where the piston is in an inward position prior touse, advantageously affecting the product's packaging efficiency. Aneedle safety feature and a syringe disabling feature may beincorporated with this arrangement. US Pat. Publication No. 2009/0221962teaches a retractable syringe and plunger. The syringe has a barrel, aretractable needle mount to which is mounted or is mountable a needle,and a plunger, the plunger comprising an initially compressed spring, ameans for engaging the retractable needle mount, an integrally formedplunger seal and a removable controlling means for facilitating controlof the rate of retraction of needle mount when engaged with plunger. Theneedle mount is held in the barrel by a holding means which preventsinadvertent retraction of the needle mount when the plunger is withdrawnto fill the syringe. The holding means comprises a plurality of clipsthat may be integrally formed with the barrel or may be present on a capmounted to the barrel. An ejector means is also provided, wherebyplunger depression can urge the ejector means to release the needle fromthe holding means and thereby allow retraction of the needle mountfollowing decompression of the spring. In one arrangement of the presentdisclosure the cartridge is associated with a syringe with a retractableneedle mount such as the one taught by US Pat. Publication No.2009/0221962.

FIG. 14 shows a cartridge 133 comprising a valved port 141, connectedwith a syringe 131. For the step of loading the syringe barrel with thedispensable product from the cartridge 133, the Luer cap 142 ismaintained in place. After merging the compartments of the cartridge 131and popping the barrier between the merged compartment and thedispensing port 141, the valved port 141 provides that when thesyringe's piston is retracted, the dispensable product will flow fromthe cartridge 133 to the syringe barrel, and when the piston isadvanced, the dispensable product is urged to the syringe tip, and willnot return to the cartridge. In one arrangement, the valved portcomprises a check valve allowing fluid to flow out of the cartridge 133,and prevent reversed flow into the cartridge 133. In one arrangement,the valved port is manually operated, for instance by rotation, axialmovement, or a combination of these, to switch between an open state toa closed state.

In some arrangements, the cartridge is removable either during themanual operation or post that. U.S. Pat. No. 7,879,018 teaches a numberof manifold arrangements for accomplishing the same and is incorporatedherein in its entirety by this reference. In some arrangements, thesyringe 131 is valved such that no flow is allowed through the syringe'stip when the syringe's piston is retracted, and flow is allowed to flowout of the syringe's barrel when the piston is advanced. In somearrangements, said syringe's valve is a check valve. In somearrangements, the syringe's valve is manually operated. In somearrangements, the syringe's valve and the cartridge's valved port 142are mechanically linked such that the operating the cartridge valvedport 142 to shutoff, operates the syringe's valve to open, or viseversa. The arrangement of FIG. 14 may be particularly advantageous wherethe dispensing tip is in a fashion that can not accept a cartridge, forinstance where the dispensing tip incorporates a staked needle, aretractable needle, or other safety mechanisms.

US Pat. Publication No. 2011/0015572 teaches a retractable syringe,plunger and releasable needle retaining assembly. The retractablesyringe typically has a glass barrel and is prefilled with fluidcontents before use. The releasable needle retaining system comprises aretractable needle, a needle seal, a retaining member and an ejectormember that is operable to release the retractable needle from theretaining member. The retaining member has a mating surface for mountingto a complementary mating surface of an interior wall of a syringebarrel. The plunger comprises a plunger outer, a plunger rod frangiblyconnected to a controlling member, a spring and a unitary plunger sealcapable of engaging the retractable needle, wherein the plunger rod,plunger outer and the controlling member co-operate to releasablymaintain the spring in an initially compressed state. After delivery offluid contents of the syringe, the plunger forces the ejector member torelease the retractable needle from the retaining member. Decompressionof the spring at the end of depression of the plunger facilitatesretraction of the retractable needle when engaged with the unitaryplunger seal. Dual locking systems prevent reuse of the syringe afterneedle retraction. In one arrangement of the present disclosure, thecartridge 133 is associated with the barrel of a safety syringe such asthe one taught be US Pat. Publication No. 2011/0015572, via a valvedport 141 arrangement of FIG. 14.

Referring now to FIG. 15, in some arrangements it is desired tolyophilize (freeze dry) a substance directly in compartment 15. Thefirst wall 18′ is pre-formed and welded to the flat, second wall 18″.The first compartment 15 is open ended and longer than the final, sealeddimensions of this compartment. The compartment allows 15 enough forfilling a liquid substance. The cartridge is then placed in a freezedrier until the lyophilization process is completed, leaving a dry cakeat the bottom of the first compartment 15. The compartment is thensealed to aseptically contain the lyophilized dose. The secondcompartment 16 may be filled and sealed prior to the lyophilizationprocess or after it.

Referring to FIG. 16, a further arrangement of a cartridge 160 is showncomprising a first 15 holding a first substance, and a secondcompartment 16 holding a second substance; the compartments areseparated by a frangible seal 19′ that is rupturable to allow the firstsubstance and the second substance to merge. The second compartment 16is separated from a female Luer Lock fitment 12 by a second frangibleseal 19″ that is rupturable to allow fluid communication between thecartridge and a dispensing device such as a syringe or an injector. Thefitment 12 comprises a fluid passageway 161, and a static mixer 162disposed in said fluid passageway 161. The arrangement is such that whenthe merged first substance and second substance are transferred fromcartridge 160 to a dispensing device the static mixer enhances themixing of these substances to form a more homogeneousness product. Anexample of a static mixer is taught in U.S. Pat. No. 4,538,920incorporated herein in its entirety by this reference. The mixture mayfurther be transferred back and forth between the delivery device andthe cartridge to repeat the mixing action at the static mixer. In somearrangements, the static mixer is constructed as a pattern ofpassageways formed between the walls of the flexible package by weldingand pre-forming designated areas of the walls. The static mixer may bemerely a narrow nozzle, or a porous component accommodated in the flowpassageway between the cartridge and the delivery device.

FIG. 17 shows a preferred embodiment in which the cartridge 170comprises a compartment 171, containing a first substance, and separatedfrom a female Luer Lock fitment 12 by a frangible seal 19″. The fitmentcomprises a fluid passageway 161 and a static mixer 162 disposed in saidfluid passageway 161. A syringe 173 containing a second substance 174 isattached to the cartridge 170. The frangible seal 19″ is rupturable toallow the first substance and the second substance to merge. By drawingthe syringe piston the first substance is drawn out of the compartment171 into the syringe and merges with the second substance in thesyringe. The syringes piston may be operated back and forth to transferat least a portion of the mixture into and from the cartridge 170, andcreate a more homogenous mixture as the material flows through thestatic mixer 162. In one arrangement, the compartment 171 issufficiently expandable to receive the total volume of the firstsubstance and the second substance. In some arrangements, the cartridge171 may comprise more than one compartment that may be merged with thefirst compartment 171 before or after merging the first compartment withthe syringe. It will be obvious to those skilled in the art that astatic mixture may be implemented in any of the previous arrangements ofthis disclosure in similar arrangements to that of FIG. 16 or FIG. 17.In particular, referring back to FIGS. 3 and 4, the static mixer may bedisposed in the syringe's stem or plunger.

FIG. 18 shows another arrangement of a cartridge 180, comprising a firstcompartment 15, containing a first substance; a second compartment 16containing a second substance; a static mixer 184, disposed between thefirst compartment 15 and the second compartment 16, and separated fromthe first compartment 15 by a frangible seal 181, and from the secondcompartment 16 by a frangible seal 182. At the point that the firstsubstance and the second substance are to be mixed, the first frangibleseal 181 and the second frangible seal 182 are ruptured such that theupper wall 183 is rearranged as indicated by dashed line 183′ to allowthe first substance and the second substance to communicate via thestatic mixer 184. The first compartment 15 and the second compartment 16are not fully inflated as the first recessed area 185 of the firstcompartment 15, and the recessed area 186 of the second compartment canexpand to receive substance from the other compartment; hence a goodmixture of the first substance and the second substance may be achievedby alternately compressing the first compartment 15 and the secondcompartment 16, and transferring the mixture of the first and secondsubstances through the static mixer 184. The static mixer 184 is shownhere as a porous body, and alternatively be other static mixer known inthe art.

A third frangible seal 19″ is rupturable to establish communicationbetween the mixture and the fitment 12. The arrangement further comprisea backing 187, supporting the cartridge 180; and a rocker, comprising afirst compression panel 188′ and a second compression panel 188″,movable to rotate relative to the backing 187, to alternately depressthe first compartment 15 with the first panel 188′, and the secondcompartment 16 with compression panel 188″. The rocker and backingarrangement facilitate an efficient operation of the mixture process bymore efficiently and systematically compressing the compartments 15 and16 and transferring the content across the static mixture 184. At thepoint that the mixture is ready to transfer to a dispensing devicethrough the fitment 12, the first compression panel 188′ may be restingwhere the first compartment 15 is depleted, thus substantially all ofthe mixture is expressed from the second compartment 16 to the fitment12. The rocker may be associated with the backing 187 via a hinge or aliving hinge, and it may be operated manually or by a device.

FIG. 19 shows another arrangement of a cartridge 190 comprising a firstcompartment 15, containing a first substance; a second compartment 16,containing a second substance; and an array of pre-formed intercrossingchannels there between, providing a static mixer, to enhance the mixingof the first and second substances as they are transported back andforth between the first compartment 15 and the second compartment 16.

Referring now to FIG. 20a to 20e , one possible manufacturing process ofthe cartridge is described. In one arrangement, this manufacturingprocess is accomplished on a Form-Fill-seal system

FIG. 20a shows a pre-formed flexible wall 18′ of a package for storingconstituents of a beneficial agent, comprising a first cavity 15, forreceiving a first constituent; a second cavity 16, for receiving asecond constituent; and a first uninterrupted area 19′ there between; afitment cavity for receiving a fitment; and a second uninterrupted area19″ between said second compartment 16 and said fitment cavity 203. Thefirst compartment is made to receive a non-fluidic material or a poorlyflowing material such as powder, compressed or agglomerated powder,granules, pellets, solid, tablet, capsule, slurry, paste, high viscousfluid, emulsion, and a combination of the above. The first substance isfilled to the first compartment by an appropriate filling system to thetype of material that needs to be filled. The second compartment 16 mayalso be filled with water or other low viscosity fluids however it maybe challenging to fully fill cavity 16 as surface tension and otherproperties of the fluid may result in spillage.

Another challenge is that liquid filling is a relatively slowmanufacturing process for a number of factors, one of which is avoidingfoaming or bubble formation as the liquid is filling the cavity 16. Inone arrangement, this challenge is addressed by freezing aliquots offluid in a mold preferably having the second compartment 16 shape, thenhandling those as solids into the cavity by one of the means known inthe art. The filling system is designed such that heat transfer to thefrozen liquid aliquots is limited such that it stays substantially soliduntil the second cavity 16 is sealed; thereafter the frozen liquid maybe thawed. Heat transfer to the frozen aliquots during the fillingprocess may be limited by controlling the temperature throughout thisprocess substantially low; and by selecting contact material to thepackage with an appropriate heat transfer coefficient. The frozen liquidaliquot may be inspected for weight and other properties and parametersprior to introduction to the second cavity 16.

In one arrangement, more than one frozen aliquots is filled to thesecond compartment 16, which may have the same, similar or differentcompositions. These aliquots may have complementary shape that mayjointly form substantially the shape of the second compartment 16. Inone arrangement, the aliquot is frozen directly in the cavity 16 or onthe reciprocal flat wall 18″ (not shown) of the package. In anotherarrangement, the second substance is a loose powder or other form ofdispersible dry substance which may be challenging for substantiallycomplete fill of the second compartment 16. Loose powder filling mayalso be a limiting factor of the manufacturing speed and a challenge forproper inspection of the aliquot fill dose. In one arrangement, in orderto facilitate the powder filling, the powder is slightly compressed toform a loosely aggregated tablet, or a unitary body, and is filled inthat form into the compartment of the package, by one of the tabletfilling means known in the art. A dedicated formulation may be requiredto achieve the level of aggregation at a given compression rate. Thetablet may be inspected prior or during the fill process of the secondcompartment 16.

In one arrangement, after the tablet has been sealed in the compartment,the compartment is externally manipulated to de agglomerate the tablet,thus improving the substance solubility (or dispersability) at the timeof mixing with a dilutent. The external manipulation may includedirecting energy to the unitary body through the wall of the package viaat least one of, but not limited to, compression of the compartment;vibration including, ultrasonic vibration, radio frequency vibration,acoustic vibration; applying mechanical impact to the compartment; andexposure to high or low temperatures. In one arrangement, the unitarybody is formed directly in the cavity 16 or on the reciprocal flat wall18″ (not shown) of the package. The first compartment 15 providesanother arrangement for efficiently filling a low viscosity fluid tosubstantially fill the cavity 15. A first filling well 201′ and a secondfilling well 201″, are pre-formed in the first wall 18′; and the firstpre-formed filling channel 202′, and second pre-formed filling channel202″ are connecting them to the first compartment 15. FIG. 20a shows aportion of a web formed to include the details of one cartridge. Itwould be understood to those skilled in the art that in a normalmanufacturing practice an array of details for multiple cartridges maybe formed on a larger spread of the first web 18′; and may be handledsimultaneously at subsequent forming and filling steps.

FIG. 20b shows a subsequent step of the manufacturing process of thecartridge 200. After the second compartment 16 (in this Figure at theopposite side of the cartridge 200) has been filled and is hermeticallysealed with a lid web 18″. The web 18″ is sealed to the entireuninterrupted surface of the first wall 18′. In one arrangement, theinner layer of the first web 18′ and/or the second web 18″ comprises anadhesive with controllable peeling (adhesion) force, where a lowersealing temperature (for instance 375° F.) results in a peelableadhesion (“frangible seal”); and a higher sealing temperature (forinstance 450° F.) results in a permanent non-peelable adhesion. In onearrangement, at the first sealing step shown in this Figure,substantially all of the uninterrupted surface of web 18′ is adhered tothe second web 18″ to form a frangible seal which completelycircumference the second compartment 16, and substantially circumferencethe first compartment 15, with the exception of the filling channels202′ and 202″. With the second web 18″ now attached to the first web 18′a filling compartment and exhausting compartments are now formed,communicating with the first compartment 15 via channels formed betweenthe two webs.

The first filling hole 204′ and the second filling hole 204″ may bepre-formed in the second web 18″ prior to its introduction to the firstwall 18′ by one of the means known in the art such as punching,die-cutting, and laser cutting. In one arrangement, the firstcompartment is filled with a first substance through the first fillinghole 204′ while the second filling hole 204″ allows for evacuation ofgasses from the first compartment 15 during filling. A filling sourcemay be associated with at least one of the filling holes 204′ and 204″during the filling process to facilitate the introduction of a substanceto the first compartment, and drawing the gases through the exhaustcompartment. In one arrangement, the filling coupler is a needle or atube that is bent to reach into the first filling channel 202′.

In one arrangement, the filling coupler has a cylindrical tip with adiameter greater than that of the filling hole 204′ such that it tightlyfit and liquid tight seals when introduced to the filling hole 204′. Inone arrangement, the filling holes 204′ and 204″ are not pre-formed, anda sharp filling object (such as a hollow needle) pierces through thesecond wall 18″ in a fluid tight fashion, into filling wells 201′ and201″. This last arrangement is particularly beneficial as the package ishermetically sealed prior to the introduction of the constituent whichcan be performed on a different portion of the filling line or on adifferent line. The packages may be stacked between the sealing step andthe filling step. In one arrangement, a rubber or semi rigid seal isdisposed in at least one of the filling wells 201′ and 201″ forming aninterface to the filling source to facilitate the sealing of the fillingcouplers to the cartridge. In one arrangement, the channels' crosssection is sufficiently small to prevent the filled substance fromspilling out of the first compartment 15, due to surface tension of thesubstance.

In one arrangement, a check-valve is disposed in at least one of thefirst and second filling wells 201′ and 201″ to control the flow of asubstance into the first compartment 15. A semi permeable object may bedisposed in one of the filling ports 201 and the filling channels 202,to allow gasses to escape during filling, and prevent the substance fromleaving the first compartment 15. In one arrangement, the flowevacuating the first cavity 15 during filling is monitored and fillingis discontinued when the evacuating fluid switches from gas to thefilled substance. The first filling channel 204′ is made such that thesubstance entering the first compartment is gliding on the second wall18″ and thus preventing jetting that may result in undesired bubbles orfoaming of the filled dose. A dedicated flow deflector may be disposedin the filling channel 202 or the filling well 201 to facilitate thegliding of the filled substance on the wall of the first compartment 15.

FIG. 20c shows a subsequent step of the cartridge 200 manufacturing. Ina second welding step the channels (202′) and (202″) are depressed andwelded, completely sealing the first substance in the first compartment15. The sealing temperature may be higher than the frangible sealwelding temperature to avoid rupture of the channels (202′) and (202″).In one arrangement, this sealing step is further applied to thecircumference of the cartridge 200, applying permanent seal propertiesto at least some of the areas that were earlier sealed as a frangibleseal. A sealable insert may be disposed in the channels to facilitatewelding and sealing of the channels.

Referring now to FIG. 20d the cartridge is trimmed from the web marginsby one of the means known in the art including punching, ruler steelcutting, laser cutting, etc.

It would be understood to those skilled in the art that themanufacturing steps order disclosed above may be switched over in wholeor in part to best suit a particular design, application, andmanufacturing equipment.

The fitment 12 is welded to and between the first wall 18′ and thesecond wall 18″ prior or during the frangible seal welding step, prioror during the permanent seal welding step, or at a subsequent step byone of the fitment welding means known in the art including, forexample, heat stake welding, impulse welding, vibration, ultrasonic, RFwelding, and light beam welding.

FIG. 21a shows an exploded view of a syringe 210 comprising a staticmixer for mixing substances. In one arrangement, a first substance iscontained in the syringe 210 and a second substance is transferred froma cartridge (not shown) to the syringe, where it is mixed with the firstsubstance. In another arrangement, at least a first substance and asecond substance are transferred to the syringe from one or morecartridges (or from a different source of the substance), separately orpre mixed, where a mixture process is applied to said substances ormixtures. In some arrangements, a cartridge is associated with thesyringe 210 in a similar fashion to that of the arrangements of FIG.2,3,4, 13 or 14. A plunger 214 is moveably disposed in the syringebarrel 212, in a fluid tight fashion. A piston 213 is concentricallydisposed in a movable fashion in the annular bore of the plunger 214 ina fluid tight fashion; the piston further comprises a static mixingplate (or static mixer) 217, laterally extending from the distal end ofthe piston 213. A local axial groove 215 in the annular bore of theplunger 214 is made to receive laterally protruding detent tooth 216 ofthe piston 213.

FIG. 21b shows a section view of the mixing syringe 210 containing afirst substance 218.

FIG. 21c shows a section view of the mixing syringe 210 where the pistonis retracted toward the proximal end of the barrel 212. The static mixerpushes the plunger the plunger along with the piston allowing a secondsubstance to enter the barrel 212 to form mixture 218′. The source ofthe second substance is not shown, however as described above it may bea cartridge associated with the syringe 210 in one of the arrangementprovided in this disclosure. It is understood that if the secondsubstance is not entering the syringe 210 from the Luer tip, the Luertip is sealed with a cap, a closure, a valve or another means such thatno flow from the tip occurs during the piston retraction.

FIG. 21d shows a mixing step where the piston 213 is moved back andfourth diverting the mixture 218′ to flow through the openings in thestatic mixer 217 and enhance the mixing of the mixture 218′ to form ahomogeneous product. The detent tooth 216 is aligned with the axialgroove 215 (not shown) such that the piston is freely movable relativeto the plunger 214. The plunger is free to glide along the barrel andcompensate of the piston's stem as it moves into and out of the sealedvolume between the barrel 212 and the plunger 214. In one arrangement,the piston is rotatable to further enhance the mixing. In onearrangement, the static mixing plate is replaced with another staticmixer known in the art such as a porous material. In one arrangement,the piston is operated by a device such as a controlled electricactuator. The syringe tip and other ports to the syringe are preferablytapped during the mixing process to avoid mixture 218′ spillage orintroduction of materials into the barrel 212.

FIG. 21e shows the syringe 210 as the piston is retracted, such that thedetent tooth 216 enters axial groove 215 (not shown); and the piston isrotated such that the detent tooth 215 engages with the radial groove219 of the plunger 214, at which position the plunger 214 and the piston213 are firmly engaged and are moveable as one. In one arrangement, thebarrel and plunger comprise a non axi-symmetric cylindrical profile toprevent the rotation of the plunger due to the piston 213 rotation. Inone arrangement, the plunger 214 comprises a rigid core to facilitatethe engagement with the piston 213. As the syringe's 210 tip isuntapped, the mixture 218′ is dispensed by advancing the piston 213 andplunger 214 toward the distal end of the syringe 210.

FIG. 22a , and the partial cross-section in FIG. 22b , illustrate acartridge associated with a staked needle syringe. The cartridge 10comprises a first substance compartment 15 and a second substancecompartment 16 separated by a rupturable barrier 19′. The cartridge 10further comprises a fitment 222, for communicating the content of thecartridge 10 with a staked needle syringe 221. The proximal end 224 ofthe fitment 222 is sealed between the first wall 18′ and the second wall18″ of the cartridge 10, and is separated from the second compartment 16by a rupturable barrier 19″, formed by directly sealing the first wall18′ and the second wall 18″. The distal end 223 of the fitment 222 ismade to removably receive the tip of the syringe 221 in a fluid tightfashion; and the proximal end 224 of the fitment 222 is made to receivethe tip of the needle 225, and protect it. A passageway 226 in thefitment 222 communicates between the needle and the content of thecartridge 10. The cartridge 10 provides an aseptic needle protector tothe needle 225.

In one arrangement, the original needle protector (not shown) is removedfrom the syringe and is replaced by cartridge 10. The content of thecartridge 10 is transferred to the syringe 221 after the second barrier19″ has been ruptured. In some arrangements, the cartridge 10 is mountedon the syringe during the manufacturing process. In one arrangement, thecartridge 10 has only a single compartment. In one arrangement, thecartridge has at least two compartments that are merged prior totransferring the content of the cartridge 10 to the syringe 221. In onearrangement, the syringe 221 comprises a safety mechanism which, at theend of the injection, retracts at least a portion of the needle 225 to aposition which protects from needle sticks. In one arrangement, thesyringe 221 comprises a needle stick safety mechanism that at leastpartially protects the needle tip after the injection of the content hasbeen completed.

Typically with pre-fillable syringes, the syringes are supplied to thefilling process disassembled and the syringe is fully assembled afterthe content has been filled. The arrangement of FIGS. 22a and 22bprovides for an advantageous manufacturing method whereby (a) thesyringe 221 is supplied assembled and finished, (b) the cartridge 10 isfilled and sealed with the desired content, and (c) the cartridge 10 isassembled. This process may be completed in an aseptic environment orthe product may be terminally sterilized. Thus, the approach allows forproducing a prefilled syringe assembly which does not require the actualsyringe components assembly. In addition, the cartridge, may be markedand labeled with the content information with our needing a specialsyringe label or package to provide this information. A label, or aportion of a label of the cartridge 10, may be transferable to thesyringe, to maintain the product identification after the cartridge 10has been removed.

FIGS. 22a and 22b illustrates the cartridge 10 with two mergeablesubstance compartments, however it would be obvious to those skilled inthe art that the cartridge 10 may include merely one compartment on morethan two compartments. The connection between the syringe 221 and thefitment 222 is shown as a fluid tight slip fit however other fittingfeatures may be incorporated to facilitate the seal, the assembly, orthe dismantle, including, for example, a thread, a helical ramp, a Luerfit, a Luer-Lock fit, an O-ring, a rubber seal component, aninterlocking feature, a snap feature, other features known in the art tofacilitate a fluid tight, removable connection, or a combination of theabove. The distal end 224 of the fitment 222 may tightly fit around theneedle 225, providing a fluid tight seal that prevents the content ofthe cartridge 10 from reaching to the space between said fitment 222 andthe needle 225; and prevent air from reaching into the needle from thatarea. The fitment may be at least partially made from elastic material.It would be obvious to those skilled in the art that the fitment 222 maybe designed such to accommodate the cartridge 10 in differentorientations relative to the syringe, and in one arrangement thecartridge 10 and the syringe 221 may at least partially overlap or restside by side. The syringe's 225 piston and barrel may be sealed at theirproximal end by an aseptic membrane 229 such that the content contactsurfaces will remain sterile without needling a sterile overwrap untilthe time of use.

Referring to FIG. 23a and its scaled-up partial section view in FIG. 23b, another preferred arrangement of a cartridge and a staked needlesyringe is illustrated. A staked needle adapter 237 is axially disposedaround the needle 225 and is connected to the tip of the syringe 221 ina fluid tight fashion. The adapter 237 protects the needle from physicaldamage, and the operator and subject from accidental needle sticks. Thedistal end of the needle 225 is further supported by a centering glider238, coaxially, movably disposed in the adapter 237 and around theneedle 225. The fitment 232 of the cartridge 10 comprises a proximalsection 234 attached to the cartridge walls, and a distal end 233 havingan elongated cylindrical, that can be axially inserted to the syringeadapter 237. With this arrangement the needle 237 remains protecteduntil the assembly with the cartridge 10.

FIG. 23c and its scaled-up partial section view in FIG. 23d illustratesthe arrangement of FIGS. 23a and 23b when the syringe assembly 231 andthe cartridge assembly 10 are engaged. The distal end 233 of the fitment232 is inserted into the adapter 237, pushing the centering piece 225 toexpose substantial portion of the distal end of the needle whichpenetrates the fitment passageway 236, establishing fluid communicationbetween the syringe 221 and the cartridge 10. A fluid tight seal may beprovided by a tight fit between the needle 225 and the fitment 237. Thefitment 237 may be at least partially made from elastic material toenhance the seal with the needle 225. The fitment 237 may furtherinclude a membrane sealing the distal end 233 or elsewhere along thepassageway 236, further enhancing the seal between the fitment 237 andthe needle 225, as well as further maintaining the cleanliness of thepassageway 236 until it is assembled with a cartridge 10.

The content of the cartridge 10 is drawn into the syringe 221.Alternatively to the seal between the needle 225 and the fitment 237, aseal can be established between (a) the centering piece 238 and theadapter 237, (b) the centering piece 238 and the needle 225, (c) thesyringe's 221 tip and the adapter 237, and (d) the fitment 232 and theadapter. In some arrangements, two substance compartments or more in thecartridge 10 are merged and allowed to mix before the content istransferred to the syringe 221. In some arrangements, substance in thesyringe 221 is transferred and merged with a substance in the cartridge10, before drawing the merged product. For example the cartridge 10 maycontain a dry substance, and the syringe 221 may contain a dilutent; thedilutent is transferred tot the cartridge 10 and allows the powder todissolve, and; the merged product is either transferred beck to thesyringe, dispensed to a subject, or transferred to another device. Inone arrangement, the syringe is prefilled with a substance, and thecontent of the cartridge 10 is transferred to the syringe 221, allowingit to merge with the substance in the syringe 221.

FIG. 23e , and its scaled-up partial section view in FIG. 23f ,illustrates the arrangement of FIGS. 23c and 23d , when the cartridge isremoved. The adapter 237 remains on the cartridge 10, and the needle isexposed as the syringe 221 is now ready for injection. In onearrangement, mechanical interlock ensures that the adapter 237 remainswith the cartridge 10. Such mechanical engagement may include a thread,a helical ramp, a snap, a tight fit, or other engaging and disengagingfeatures known in the art. In one arrangement, the adapter 237 remainson the syringe 221 when the cartridge 10 is removed, to continueproviding protection to and from the needle 225; and it is removed priorto injection by the operator.

FIG. 24 illustrates another arrangement similar to the arrangement ofFIG. 23 with the exception that a rubber septum 241 is disposed on thetip of the needle, and a spring 242 biases the centering piece 220 andthe septum 241 toward the distal end of the adapter 237. The needle isaseptically sealed by the septum 241. For transferring material betweenthe cartridge 10 and the syringe 221, the distal end 233 of the fitment232 is introduced into the adapter 237, displacing the septum andcentering piece backward, and exposing the tip of the needle 225 to thepassageway 226 in the fitment 232. When the cartridge 10 is removed, thespring 242 causes the septum to return to cover the tip of the needle225, providing protection from mechanical damage and contamination tothe needle 225 until the time of use. The adapter 237 is removed withthe spring 242, the centering piece 220, and the septum 241 prior to useof the syringe 221.

FIG. 25a illustrates a prefilled cartridge comprising a coupler 250 anda package associated via the fitment 257. The coupler assembly comprisesa needle assembly 253 comprising a Luer Lock hub 255 and a stainlesssteel cannula 254 attached to the hub. The needle assembly (or needle)253 is accommodated in a needle cap formed in the coupler 251. Thecoupler further comprises a fluid passageway 258 for communicating theneedle 253 with the package 10. A rubber sheath 252 disposed in saidcoupler 251 forms an aseptic seal between the needle hub 255 and thecoupler. The tip of the rubber sheath 252 forms a fluid tight closure ofthe fluid passageway 258, which is pierced by the cannula 254 toestablish fluid communication between the needle 253 and the package.The Luer end 256 of the needle hub 255 is sealed with a removableaseptic closure either in the form of a sealed foil, a closure or othermeans known in the art. The package 10 comprises a first rupturablebarrier 19′ segregating between a first compartment containing a firstconstituent and a second compartment 16 containing a second constituent,said first and second constituents are allowed to merge when therupturable barrier is ruptured. In another configuration, the package 10comprises a single constituent of the beneficial agent. In yet anotherembodiment the package comprises at least a third compartment comprisinga third constituent segregated from the second or the first compartmentsby a rupturable barrier. A second rupturable barrier 19″ provides aclosure between the second compartment 16 and the fitment 257 leading tothe passageway 258 in the coupler 251.

FIG. 25b illustrates the arrangement of FIG. 25a after the first and thesecond rupturable barriers have been opened, allowing the first andsecond constituents to merge, and establishing fluid communication ofsaid mixture 16′ with the needle 253 via the coupler 251. Thearrangement provides a simple prefilled cartridge that can be mounted ona standard Luer syringe 259 via engagement of the female Luer connectorof the needle 253 with the male Luer of the syringe 259. The product 16′can then be taken into the syringe by retracting the syringe's piston,which after the coupler may be removed to expose the needle 253 forinjection as shown in FIG. 25c . In one configuration, the syringe maycontain a third constituent that may be merged with the product 16′either by drawing the product 16′ into the already partly filledsyringe, or by first dispensing said third constituent from the syringeto the package 10 and secondly draw the mixture back to the syringe orto a different delivery device. The coupler 251 further provides abacking for part of the package 10.

FIG. 26 illustrates a prefilled unit-dose aseptic reconstitutioncartridge comprising a package 10 adopted to communicate with a syringe260, comprising an intradermal (ID) injection adapter (ID Adapter),comprising a forwardly protruding skid 264 facilitating a shallowinsertion of the needle 262 to the skin. US Pat. Publication Nos.2010/0137831 and 2011/0224609 are teaching similar arrangement of anadapter to facilitate intradermal injection and are incorporated hereinin their entireties by this reference. The ID adapter may be an integralportion of the syringe 261 or a clip on, forming an ID syringe. A recess267 is formed in the skid 264 to facilitate the introduction of thefitment 265 of the package 10 onto the needle hub 266 of the syringe260.

FIG. 27a illustrates the cartridge 10 mounted on an ID syringe where thecartridge 10 and syringe 260 are positioned in a linear arrangement. Theview provides an orientation of the section view of FIG. 27b . FIG. 27billustrates the fitment 265 press-fitted on the needle hub 266 formingan aseptic connection. A rubber stopper provides a closure to passageway272 and is pierced by needle 262 to establish fluid communicationbetween the syringe and the package 10.

FIG. 28 illustrates a similar arrangement to that of FIG. 10 with theexception that the fitment 281 is made such that the package 10 ispositioned parallel to the syringe barrel instead of in line with thesyringe axis.

FIGS. 29a and 29b illustrates a cartridge configuration comprising acoupler 293 communicating an intradermal needle assembly 291 and thepackage 10. The coupler accommodates a needle assembly comprising acannula 292 and a needle hub 291 comprising the forward protruding skidat its distal end and a Luer connector at its proximal end 297. Thecoupler 293 is used as an aseptic cap engaged with the needle hub 291 insealing area 299 maintaining the needle 292 and the skid area sterile. ALuer cap 298 is aseptically sealing the Luer connector 297 of the needlehub 291 forming an integrally sealed cartridge which remains sterilewithout the need of a sterile overwrap. The package 10 and the couplerare connected via the fitment 296. The fitment is preferably heat weldedto the wall of the package 10, and is connected to the coupler by one ofthe means known in the art including heat welding, bonding, or a tightmechanical fit. The rupturable seal 19 between the first compartment 15and the second compartment 16 provides a closure segregating saidcompartments from the coupler 293.

FIG. 29b illustrates the arrangement of FIG. 29a where the Luer cap 298is replaced with a Luer syringe 250, the rupturable seal is openedallowing the constituents in the first and second compartments 15,16 tomerge and establishing fluid communication with the needle viapassageway 295. The rubber closure 294 limits the dead space of theconstituents in the coupler to the minute volume of passageway 295, thuslimiting waste of the product 15′. The Figure is showing the piston ofthe syringe retracting to receive the product 15′ in the syringe'sbarrel. The coupler is removed to expose the needle and the ID adapterfor injection. The coupler 293 provides a backing to the package 10facilitating depression of the compartments of the package 10.

FIG. 30 illustrates a cartridge arrangement 300 similar to the cartridgearrangement 290 of FIG. 29 with the exception that the ID adapter 291 ismounted on a needle hub 301. The needle hub 301, the ID adapter 291 andthe coupler 293.

FIG. 31a shows a cartridge 310 having an arrangement that is mostlysimilar to the arrangement 300 of FIG. 30 with the exception that theneedle hub is moveably disposed in the ID adapter 313, moveable betweenan injection position and safe-discard position. A latch mechanism 315retains the injection position. A spring may be disposed in area 312 tobias the needle hub 313 to the safe-discard position. FIG. 31billustrates arrangement 310 when the latch has been operated to releasethe needle hub. The needle assembly is retracted bringing the needle tipto a confined section 316 reducing the risk of needle sticks. In onearrangement the needle hub is permanently locked in this position toprevent repeated use of the needle.

FIG. 32 shows a cartridge arrangement 320 similar to arrangement 290 ofFIG. 29 with the exception that the needle assembly is movably disposedin the coupler, and is moveable between a first position where theneedle tip 292 does not pierce the stopper 294, or is only partlypiercing the stopper, to a second position where the needle tip piercesthe stopper to establish fluid communication with the fluid passageway295.

FIG. 33a to FIG. 33c illustrates a prefilled syringe 259 comprising aregular piston-and-barrel syringe arrangement with a staked needle 334for delivering medication. A syringe cap 331 communicates with thesyringe in an aseptic engagement. The cap 331 is engaged with a package10 to form a removable cartridge 330. The body of the cap 331 operatesas a coupler between the fitment of the package and the needle. FIGS.33d and 33e show an scaled up section view of the cap during storage andafter activation as the dose is being filled to the syringe's barrel.The cap comprises a rubber stopper 335 that is pierced through by theneedle 334.

It would be obvious to those skilled in the art that similarconfigurations are operative with other needle arrangements known in theart including, syringe with catheter, needle with protective softsheath, intramuscular (IM) needle, Subcutaneous (SQ) needle, Intradermal(ID) needle, micro-needle, safety needles, retractable needle,irrigation needle, etc.

The syringe further comprises a an aseptic closure 333 to the barrelsuch that this syringe assembly maintains sterile without the need of asterile overwrap.

FIG. 37 illustrates an arrangement similar to the arrangement of FIG. 33with the addition of protective walls 341 vertically protruding toprotect the package 10. It will be obvious to those skilled in the artthat the protection of the package can be enhanced by furthersurrounding the package with additional wall, a flip-over coverassociated with the wall 341, a slideable cover, etc.

The packages of the arrangements of this disclosure may carry anymarking including printing, barcoding, RFID tags, embossment, andengraving to communicate desired information with a person or a device.The package may be extended to provide sufficient marking surface asneeded.

A compression panel may be associated with the package to facilitatedepression of at least one compartment of the package either to urge therupture of a rupturable barrier, or to urge expression of thedispensable product from the package.

The arrangement and method described above is applicable for otherinjectors, or dispensers types such as the jet injector cartridge taughtin FIG. 1 or other arrangements discussed in this document. In onearrangement, a retractable needle mechanism, retractable needleconnector mechanism, or other needle safety mechanisms, and reusedisabling mechanism is incorporated with the mixing syringe mechanismdescribed herein.

The cartridge arrangement of the present disclosure may be combined withseveral forms of delivery devices or applicators to facilitate a desiredform of use. A compression panel or roller may be incorporated tofacilitate an efficient expression of the cartridge's content.

The applications of the present invention are not limited to the syringeand jet-injector applications which are provided here by way of example,and the teachings described herein can be applied to other applicationssuch as aseptic filling of micro-pump reservoir, intramuscular autoinjectors, intradermal auto injectors etc.

What is claimed is:
 1. A cartridge for use with a beneficial agentdelivery device, said delivery device having a fillable reservoir, saidcartridge comprising: a reconstitution unit dose package, comprising: afirst compartment containing at least a first constituent of thebeneficial agent; at least a second compartment containing at least asecond constituent of the beneficial agent; and a fitment disposed onsaid package and configured to establish a fluid interface between saidpackage and the fillable reservoir; and a coupler separate from thereconstitution unit dose package, the coupler configured to support atleast part of the reconstitution unit dose package and provide a cap forreceiving at least a delivery portion of the delivery device; wherein atleast one of the first compartment and the second compartment comprisesa flexible wall having a pre-formed structure; and wherein the couplerprovides an aseptic engagement between the package and the deliverydevice.
 2. The cartridge of claim 1 wherein the delivery portion of thedelivery device comprises one of a needle, a connector, or a nozzle. 3.The cartridge of claim 1 wherein said first compartment is segregatedfrom said second compartment by a rupturable barrier.
 4. The cartridgeof claim 1 further comprising a foil layer peelable off at least one ofthe first compartment and the second compartment.
 5. The cartridge ofclaim 1 further comprising a fluid passageway between said firstcompartment and said second compartment.
 6. The cartridge of claim 5further comprising a static mixer disposed in said fluid passageway. 7.The cartridge of claim 1 further comprising a fluid passageway betweensaid package and the delivery device, and a static mixer disposed in thefluid passageway.
 8. The cartridge of claim 1 further comprising afilling compartment in fluid communication with said first compartmentvia a fluid filling passageway.
 9. The cartridge of claim 8 wherein saidfluid passageway is sealable to prevent fluid communication between thefilling compartment and the first compartment.
 10. The cartridge ofclaim 8 wherein said filling passageway is configured to direct fluidalong a first wall of said first compartment to prevent jetting.
 11. Thecartridge of claim 8 further comprising a gas evacuation chamber incommunication with said first compartment via a fluid evacuationpassageway, said fluid evacuation passageway having a gas-permeable,liquid-impermeable seal disposed therein.
 12. The cartridge of claim 1,wherein at least a portion of said first compartment or said secondcompartment comprises a tubular construction.
 13. The cartridge of 15wherein the filling compartment is configured to form a fluid tightcommunication with a filling system.
 14. The cartridge of claim 1,wherein a periphery of said first compartment is sealed to saidreinforced backing and side walls of said first compartment extend in adirection generally perpendicular to said reinforced backing.
 15. Thecartridge of claim 1 wherein: said first compartment comprises aflexible wall having a pre-formed structure; and said first compartmentis moveable between a pre-formed state in which said pre-formedstructure defines a fillable cavity configured to receive the beneficialagent and a second deformed state in which the volume is substantiallydepleted.